Preparation method of 2-amino-6-nitrobenzamide

Abstract

The invention discloses a preparation method of 2-amino-6-nitrobenzamide (2-amino-6-nitrobenzamide). The method comprises the following specific process: carrying out ammonolysis on 2-chloro-6-nitrobenzonitrile as shown in a formula (I) under the action of a cuprous catalyst, an alkaline substance, an organic solvent and ammonia water to synthesize 2-amino-6-nitrobenzamide as shown in a formula (II). By adopting a limited technology, the use of a highly toxic reagent is avoided, and the operation safety is improved; the cuprous catalyst is adopted to replace an expensive metal cuprous catalyst, so that the method has the advantages of good reaction selectivity, mild conditions, high conversion rate, low cost and easiness in large-scale production;

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing 2-amino-6-nitrobenzamide. Background Technology

[0002] 2-Amino-6-nitrobenzamide is a key intermediate with wide applications in the synthesis of pesticides, pharmaceuticals and fine chemicals.

[0003] Patent CN115572282A reports a method for synthesizing 2-amino-6-nitrobenzamide: using 2-amino-6-nitrobenic acid as a raw material, it is first reacted with triphosgene in tetrahydrofuran at low temperature to generate 5-nitro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione, which is then reacted with ammonium carbonate in a 1,4-dioxane to obtain 2-amino-6-nitrobenzamide.

[0004] This method uses triphosgene as a reagent, which generates highly toxic phosgene in situ during the reaction, placing extremely high demands on experimental safety and operability. Therefore, this method presents high safety risks, high operational barriers, and significant environmental pressures, fundamentally limiting its potential for application in industrial-scale production.

[0005] Samanta Yadav, Rajeev Gupta, et al. reported a method for synthesizing 2-amino-6-nitrobenzamide in Inorg.chem., 2022, 61, 15463-15474: using 2-amino-6-nitrobenzonitrile as the starting material, 2-amino-6-nitrobenzamide was synthesized directly under alkaline conditions in the presence of a cuprous metal catalyst.

[0006]

[0007]

[0008] However, this method faces significant economic and technological constraints in large-scale production applications, with the main bottleneck being the design of the catalytic system. The copper molybdenum catalyst used is expensive, and its recovery is difficult and its recyclability is poor. The high initial investment in copper molybdenum catalyst and the unresolved recovery and loss problems jointly increase the overall cost of the production process, leading to additional metal residues and environmental treatment pressures. These factors severely restrict the transformation of this technology route into large-scale industrial production. Summary of the Invention

[0009] In view of the above-mentioned problems in the existing technology, the purpose of the present invention is to provide a method for preparing 2-amino-6-nitrobenzamide with good selectivity, mild reaction conditions, high conversion rate and easy large-scale production.

[0010] The specific solution disclosed in this invention is as follows: A method for preparing 2-amino-6-nitrobenzamide involves reacting 2-chloro-6-nitrobenzonitrile as shown in formula (I) with a cuprous catalyst, an alkaline substance, an organic solvent, and ammonia to generate 2-amino-6-nitrobenzamide as shown in formula (II).

[0011] The reaction equation is as follows:

[0012] Furthermore, the present invention specifies that the cuprous catalyst is cuprous oxide, cuprous chloride, cuprous iodide, or cuprous bromide, preferably cuprous oxide.

[0013] Furthermore, the present invention also specifies that the molar ratio of 2-chloro-6-nitrobenzene to cuprous catalyst is 1:0.01-0.2, preferably 1:0.1.

[0014] Furthermore, the present invention further specifies that the alkaline substance is selected from cesium carbonate, potassium carbonate, sodium carbonate, calcium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, and potassium tert-butoxide, preferably sodium carbonate.

[0015] Furthermore, the present invention also specifies that the molar ratio of 2-chloro-6-nitrobenzene to the alkaline substance is 1:1-5, preferably 1:3.

[0016] Furthermore, the present invention further specifies that the organic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, toluene, isopropanol, acetonitrile, ethanol, dimethyl sulfoxide, N-methylpyrrolidone, and preferably isopropanol.

[0017] Furthermore, the molar ratio of 2-chloro-6-nitrobenzene to the organic solvent is 1:1-20, preferably 1:5-10.

[0018] Furthermore, the present invention also specifies that the concentration of ammonia water is 20%-40%, preferably 25%-28%, and the molar ratio of 2-chloro-6-nitrobenzene to ammonia water is 1:2-20, preferably 1:10-15.

[0019] Furthermore, the present invention also specifies that the reaction temperature is 80-130℃ and the reaction time is 12-18h, preferably 90℃ and 15h.

[0020] Furthermore, the present invention also limits the reaction pressure to the conventional pressure of this type of reaction, and controls the pressure at 0.5-2 MPa, preferably 0.5-1 MPa, by adding ammonia to seal the reaction system.

[0021] By employing the above-described technology, the present invention offers the following advantages compared to existing methods: This invention uses 2-chloro-6-nitrobenzene as a raw material, and reacts directly with ammonia water to generate 2-amino-6-nitrobenzeneamide under the action of cuprous catalyst, alkali, and organic solvent. This avoids the use of highly toxic reagents as mentioned in the background art, thus improving operational safety. The use of cuprous catalysts instead of expensive metallic cuprous catalysts results in good reaction selectivity, mild conditions, high conversion rate, low cost, and ease of large-scale production. Detailed Implementation

[0022] To better understand the present invention, the following embodiments are provided for further illustration. These embodiments are for explanation only and do not constitute a substantial limitation on the present invention.

[0023] Example 1: Preparation of 2-amino-6-nitrobenzamide

[0024] 2-Chloro-6-nitrobenzenenitrile (57 mmol, 10.2 g), cuprous oxide (5 mmol, 0.71 g), sodium carbonate (0.17 mol, 15.3 g), isopropanol (0.5 mol, 30.5 g), and ammonia (0.5 mol, 34.6 g) were added sequentially to a 250 ml high-pressure reactor. The mixture was heated to 90 °C and reacted for 15 h. During the reaction, the pressure increased to 0.7 MPa. After the reaction solution was allowed to cool naturally to room temperature, the pressure was released, and the reaction solution was transferred to a beaker. The reactor was rinsed with a small amount of water and the solution was added to the main liquid. The cuprous oxide was first recovered by filtration. The reaction solution was then poured into ice water at 0-5 °C to precipitate the product. The product was filtered, and the filter cake was washed several times with a small amount of ice water to remove residual ammonium salts and ammonia. After drying, 9.1 g of 2-amino-6-nitrobenzeneamide was obtained. The yield was 89.8%.

[0025] Example 2 Preparation of 2-amino-6-nitrobenzamide 2-Chloro-6-nitrobenzenenitrile (57 mmol, 10.2 g), cuprous chloride (5 mmol, 0.49 g), sodium carbonate (0.17 mol, 15.3 g), isopropanol (0.5 mol, 30.5 g), and ammonia (0.5 mol, 34.6 g) were added sequentially to a 250 ml high-pressure reactor. The mixture was heated to 90 °C and reacted for 15 h. During the reaction, the pressure increased to 0.7 MPa. After the reaction solution was allowed to cool naturally to room temperature, the pressure was released, and the solution was transferred to a beaker. The reactor was rinsed with a small amount of water and the solution was added to the main mixture. The cuprous chloride was first recovered by filtration. The reaction solution was then poured into ice water at 0-5 °C to precipitate the product. The product was filtered, and the filter cake was washed several times with a small amount of ice water to remove residual ammonium salts and ammonia. After drying, 8.3 g of 2-amino-6-nitrobenzeneamide was obtained. The yield was 83.2%.

[0026] Example 3 Preparation of 2-amino-6-nitrobenzamide 2-Chloro-6-nitrobenzenenitrile (57 mmol, 10.2 g), cuprous iodide (5 mmol, 0.95 g), sodium carbonate (0.17 mol, 15.3 g), isopropanol (0.5 mol, 30.5 g), and ammonia (0.5 mol, 34.6 g) were added sequentially to a 250 ml high-pressure reactor. The mixture was heated to 90 °C and reacted for 15 h. During the reaction, the pressure increased to 0.7 MPa. After the reaction solution was allowed to cool naturally to room temperature, the pressure was released, and the mixture was transferred to a beaker. The reactor was rinsed with a small amount of water and the main solution was added. The cuprous iodide was first recovered by filtration. The reaction solution was then poured into ice water at 0-5 °C to precipitate the product. The product was filtered, and the filter cake was washed several times with a small amount of ice water to remove residual ammonium salts and ammonia. After drying, 7.1 g of 2-amino-6-nitrobenzeneamide was obtained. The yield was 76.7%.

[0027] Example 4 Preparation of 2-amino-6-nitrobenzamide 2-Chloro-6-nitrobenzenenitrile (57 mmol, 10.2 g), cuprous bromide (5 mmol, 0.71 g), sodium carbonate (0.17 mol, 15.3 g), isopropanol (0.5 mol, 30.5 g), and ammonia (0.5 mol, 34.6 g) were added sequentially to a 250 ml high-pressure reactor. The mixture was heated to 90 °C and reacted for 15 h. During the reaction, the pressure increased to 0.7 MPa. After the reaction solution was allowed to cool naturally to room temperature, the pressure was released, and the mixture was transferred to a beaker. The reactor was rinsed with a small amount of water, and the mixture was then added to the main solution. The cuprous bromide was first recovered by filtration. The reaction solution was then poured into ice water at 0-5 °C to precipitate the product. The product was filtered, and the filter cake was washed several times with a small amount of ice water to remove residual ammonium salts and ammonia. After drying, 6.5 g of 2-amino-6-nitrobenzeneamide was obtained. The yield was 71.1%.

[0028] Example 5 Preparation of 2-amino-6-nitrobenzamide 2-Chloro-6-nitrobenzenenitrile (57 mmol, 10.2 g), cuprous oxide (5 mmol, 0.71 g), potassium carbonate (0.17 mol, 23.4 g), isopropanol (0.5 mol, 30.5 g), and ammonia (0.5 mol, 34.6 g) were added sequentially to a 250 ml high-pressure reactor. The mixture was heated to 90 °C and reacted for 15 h. During the reaction, the pressure increased to 0.7 MPa. After the reaction solution was allowed to cool naturally to room temperature, the pressure was released, and the mixture was transferred to a beaker. The reactor was rinsed with a small amount of water and the solution was added to the main mixture. The cuprous oxide was first recovered by filtration. The reaction solution was then poured into ice water at 0-5 °C to precipitate the product. The product was filtered, and the filter cake was washed several times with a small amount of ice water to remove residual ammonium salts and ammonia. After drying, 7.9 g of 2-amino-6-nitrobenzeneamide was obtained. The yield was 78.5%.

[0029] Example 6 Preparation of 2-amino-6-nitrobenzamide 2-Chloro-6-nitrobenzenenitrile (57 mmol, 10.2 g), cuprous oxide (5 mmol, 0.71 g), cesium carbonate (0.17 mol, 53.1 g), isopropanol (0.5 mol, 30.5 g), and ammonia (0.5 mol, 34.6 g) were added sequentially to a 250 ml high-pressure reactor. The mixture was heated to 90 °C and reacted for 15 h. During the reaction, the pressure increased to 0.7 MPa. After the reaction solution was allowed to cool naturally to room temperature, the pressure was released, and the mixture was transferred to a beaker. The reactor was rinsed with a small amount of water and the solution was added to the main mixture. The cuprous oxide was first recovered by filtration. The reaction solution was then poured into ice water at 0-5 °C to precipitate the product. The product was filtered, and the filter cake was washed several times with a small amount of ice water to remove residual ammonium salts and ammonia. After drying, 7.3 g of 2-amino-6-nitrobenzeneamide was obtained. The yield was 80.9%.

[0030] Example 7 Preparation of 2-amino-6-nitrobenzamide 2-Chloro-6-nitrobenzenenitrile (57 mmol, 10.2 g), cuprous oxide (5 mmol, 0.71 g), sodium hydroxide (0.17 mol, 6.8 g), isopropanol (0.5 mol, 30.5 g), and ammonia (0.5 mol, 34.6 g) were added sequentially to a 250 ml high-pressure reactor. The mixture was heated to 90 °C and reacted for 15 h. During the reaction, the pressure increased to 0.7 MPa. After the reaction solution was allowed to cool naturally to room temperature, the pressure was released, and the solution was transferred to a beaker. The reactor was rinsed with a small amount of water and the solution was added to the main mixture. The cuprous oxide was first recovered by filtration. The reaction solution was then poured into ice water at 0-5 °C to precipitate the product. The product was filtered, and the filter cake was washed several times with a small amount of ice water to remove residual ammonium salts and ammonia. After drying, 6.5 g of 2-amino-6-nitrobenzeneamide was obtained. The yield was 71.2%.

[0031] Example 8 Preparation of 2-amino-6-nitrobenzamide 2-Chloro-6-nitrobenzenenitrile (57 mmol, 10.2 g), cuprous oxide (5 mmol, 0.71 g), potassium hydroxide (0.17 mol, 8.6 g), isopropanol (0.5 mol, 30.5 g), and ammonia (0.5 mol, 34.6 g) were added sequentially to a 250 ml high-pressure reactor. The mixture was heated to 90 °C and reacted for 15 h. During the reaction, the pressure increased to 0.7 MPa. After the reaction solution was allowed to cool naturally to room temperature, the pressure was released, and the solution was transferred to a beaker. The reactor was rinsed with a small amount of water and the solution was added to the main mixture. The cuprous oxide was first recovered by filtration. The reaction solution was then poured into ice water at 0-5 °C to precipitate the product. The product was filtered, and the filter cake was washed several times with a small amount of ice water to remove residual ammonium salts and ammonia. After drying, 6.2 g of 2-amino-6-nitrobenzeneamide was obtained. The yield was 68.2%.

[0032] Example 9 Preparation of 2-amino-6-nitrobenzamide 2-Chloro-6-nitrobenzenenitrile (57 mmol, 10.2 g), cuprous oxide (5 mmol, 0.71 g), sodium carbonate (0.17 mol, 15.3 g), dimethyl sulfoxide (0.5 mol, 39.1 g), and ammonia (0.5 mol, 34.6 g) were added sequentially to a 250 ml high-pressure reactor. The mixture was heated to 90 °C and reacted for 15 h, during which time the pressure increased to 0.5 MPa. After the reaction solution was allowed to cool naturally to room temperature, the pressure was released, and the solution was transferred to a beaker. The reactor was rinsed with a small amount of water and the solution was added to the main mixture. The cuprous oxide was first recovered by filtration. The reaction solution was then poured into ice water at 0-5 °C to precipitate the product. The product was filtered, and the filter cake was washed several times with a small amount of ice water to remove residual ammonium salts and ammonia. After drying, 6.8 g of 2-amino-6-nitrobenzeneamide was obtained. The yield was 75.8%.

[0033] Example 10 Preparation of 2-amino-6-nitrobenzamide 2-Chloro-6-nitrobenzenenitrile (57 mmol, 10.2 g), cuprous oxide (5 mmol, 0.71 g), sodium carbonate (0.17 mol, 15.3 g), N,N-dimethylformamide (0.5 mol, 36.5 g), and ammonia (0.5 mol, 34.6 g) were added sequentially to a 250 ml high-pressure reactor. The mixture was heated to 90 °C and reacted for 15 h. During the reaction, the pressure increased to 0.6 MPa. After the reaction solution was allowed to cool naturally to room temperature, the pressure was released, and the mixture was transferred to a beaker. The reactor was rinsed with a small amount of water and the solution was added to the main mixture. The cuprous oxide was first recovered by filtration. The reaction solution was then poured into ice water at 0-5 °C to precipitate the product. The product was filtered, and the filter cake was washed several times with a small amount of ice water to remove residual ammonium salts and ammonia. After drying, 6.6 g of 2-amino-6-nitrobenzenenitrile was obtained. The yield was 72.8%.

[0034] Example 11 Preparation of 2-amino-6-nitrobenzoic acid

[0035] In a 100 mL round-bottom flask, 2-amino-6-nitrobenzoamide (27 mmol, 5.1 g), 25% sodium hydroxide aqueous solution (108 mmol, 17.3 mL), and ethanol (20 mL) were added sequentially. The mixture was stirred at 90 °C for 2 hours. After the reaction solution cooled naturally, a clear solution was obtained. Concentrated hydrochloric acid was slowly added dropwise in an ice-water bath to adjust the pH to 3-4, precipitating a large amount of crude 2-amino-6-nitrobenzoic acid. The crystallization was continued in an ice-water bath for 20-30 minutes to ensure complete crystallization. The solution was filtered, washed 2-3 times with a small amount of ice water, dried, and recrystallized from ethanol to give 4.8 g of the product, with a yield of 93.5%.

[0036] The preparation method of the raw material 2-chloro-6-nitrobenzene used in this invention refers to the method in CN115108983A, and is as follows:

[0037] At room temperature, 1.05 mol (199.5 g) of 2,3-dichloronitrobenzene, 0.5 mol (24.5 g) of sodium cyanide, and 0.5 mol (44.5 g) of cuprous cyanide were added to a 500 mL reaction flask. The mixture was slowly heated to 90 °C in an oil bath. After the 2,3-dichloronitrobenzene melted to obtain a slurry, stirring was started, and the temperature was continued to rise. After reaching 100 °C, 3 mol (219 g) of DMF was added, and the temperature was further increased. The temperature was raised to 160℃ and maintained for 6 hours, then the temperature was further increased to 170℃ and maintained for 8 hours. Sampling and analysis revealed that 2,3-dichloronitrobenzene was less than 0.5%. After the reaction was complete, the temperature was lowered to 90℃, and DMF was recovered by desolvation under negative pressure. After desolvation, chlorobenzene was added to the reaction flask, stirred until fully dissolved, and then filtered at 80℃ to remove inorganic salts. The filtrate was washed with 5% ammonia water at 70℃ for 1 hour with stirring, allowed to stand, and allowed to separate into layers. The organic phase was washed once more with water. After removing the solvent by rotary evaporation and drying, 152.4 g of 2-chloro-6-nitrobenzene was obtained, with a yield of 80.6%.

Claims

1. A method for preparing 2-amino-6-nitrobenzamide, characterized in that... 2-Chloro-6-nitrobenzene as shown in formula (I) is reacted with a cuprous catalyst, an alkaline substance, an organic solvent, and ammonia to generate 2-amino-6-nitrobenzene as shown in formula (II). 。 2. The method for preparing 2-amino-6-nitrobenzamide according to claim 1, characterized in that... The cuprous catalyst is cuprous oxide, cuprous chloride, cuprous iodide or cuprous bromide, preferably cuprous oxide, and the molar ratio of 2-chloro-6-nitrobenzene to the cuprous catalyst is 1:0.01-0.

2.

3. The method for preparing 2-amino-6-nitrobenzamide according to claim 1, characterized in that... The alkaline substance is cesium carbonate, potassium carbonate, sodium carbonate, calcium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, or potassium tert-butoxide, preferably sodium carbonate, and the molar ratio of 2-chloro-6-nitrobenzene to the alkaline substance is 1:1-5.

4. The method for preparing 2-amino-6-nitrobenzamide according to claim 1, characterized in that... The organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, toluene, isopropanol, acetonitrile, ethanol, dimethyl sulfoxide, or N-methylpyrrolidone, preferably isopropanol, and the molar ratio of 2-chloro-6-nitrobenzene to the organic solvent is 1:1-20.

5. The method for preparing 2-amino-6-nitrobenzamide according to claim 1, characterized in that... The concentration of ammonia water is 20%-40%, preferably 25%-28%; the molar ratio of 2-chloro-6-nitrobenzene to ammonia water is 1:2-20, preferably 1:10-15.

6. The method for preparing 2-amino-6-nitrobenzamide according to claim 1, characterized in that... The reaction temperature is 80-130℃, preferably 90℃.

7. The method for preparing 2-amino-6-nitrobenzamide according to claim 1, characterized in that... The reaction is carried out in a closed reactor at a pressure controlled at 0.5-2 MPa.

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